Alcohol silences a key gut protein, letting harmful bacteria flood into the liver. Reactivating this pathway could protect against liver disease and offer new hope for treating alcohol dependence.
Alcohol-associated liver disease (ALD) is becoming one of the leading reasons people require liver transplants and one of the major causes of liver-related deaths around the world. The toll is rising quickly. In the United States alone, ALD resulted in an estimated $31 billion in annual costs in 2022. Projections suggest that by 2040, those costs could climb to $66 billion. Because current treatment options for ALD are limited, researchers are searching for new strategies that focus on the molecular processes driving the disease, with the goal of preventing it or reducing its progression.
Alcohol Disrupts a Key Gut Defense
Researchers at the University of California, San Diego School of Medicine have identified how long-term alcohol consumption interferes with an important cellular signaling protein that helps keep gut bacteria contained within the intestinal tract. When this protective system weakens, those bacteria can move into the liver more easily, intensifying the damage caused by alcohol. The team suggests that targeting this biological pathway with drugs already available may help limit the liver injury associated with heavy alcohol use and lessen the overall impact of ALD.
What the Researchers Found
To explore this mechanism, the scientists examined human liver biopsy samples along with mouse models of ALD. Their findings showed the following:
- Chronic alcohol use reduced the expression of muscarinic acetylcholine receptor M4 (mAChR4), a key cellular communication protein in the gut.
- Reduced mAChR4 expression hindered the formation of goblet cell-associated antigen passages (GAPs), specialized structures that teach the immune system to promote antimicrobial immunity, thereby preventing harmful bacteria from migrating to the liver.
- Restoring mAChR4 function, either by chemically activating mAChR4 or by targeting related signaling pathways allowed GAPs to form and conferred resistance to ALD.
Wider Implications for Alcohol-Related Disorders
Although the research centered on mAChR4 within the gut, this signaling protein is also known to influence areas of the brain involved in habit formation, learning and addiction. Because individuals with alcohol use disorder (AUD) tend to have lower mAChR4 expression in these brain regions, the findings may extend beyond liver disease.
Drugs that affect mAChR4 are already being tested in clinical trials for schizophrenia, and the scientists propose that such medications could potentially be repurposed for ALD and AUD. Additional studies will be needed to confirm whether this approach is viable.
Reference: “mAChR4 suppresses liver disease via GAP-induced antimicrobial immunity” by Cristina Llorente, Fernanda Raya Tonetti, Ryan Bruellman, Rocío Brea, Nuria Pell, Phillipp Hartmann, Luca Maccioni, Hui Han, Noemí Cabré, Junlai Liu, Alvaro Eguileor, Marcos F. Fondevila, Abraham S. Meijnikman, Cynthia L. Hsu, Ameera Alghafri, Rongrong Zhou, Bei Gao, Yi Duan, Peng Zhang, Mark A. Febbraio, Koji Taniguchi, Rodney D. Newberry, Derrick E. Fouts, David A. Brenner, Peter Stärkel, Michael Karin and Bernd Schnabl, 20 August 2025, Nature.
DOI: 10.1038/s41586-025-09395-z
The study, published in the journal Nature, was led by Cristina Llorente, Ph.D., Michael Karin, Ph.D., and Bernd Schnabl, M.D., at UC San Diego School of Medicine. The study was funded, in part, by the National Institutes of Health (grants R01 AA029106, R21 AA030654, P30 AR073761, D34 HP31027, P50 AA011999) and the American Association for the Study of Liver Diseases (award 8998GA). Bernd Schnabl has consulted for Ferring Research Institute, HOST Therabiomics, Intercept Pharmaceuticals, Mabwell Therapeutics, Patara Pharmaceuticals, Surrozen, and Takeda. He is also the founder of Nterica Bio.
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3 Comments
“To explore this mechanism, the scientists examined human liver biopsy samples along with mouse models of ALD.” They poisoned mice with alcohol and think the results are meaningful in any sense apart from demonstrating human cruelty.
Alcohol is a powerful solvent, and dissolves fat, which means they destroy membranes and the liver independent of intestinal bacteria. Alcohol also interferes with the action of many drugs. It would be ironic if the drug they hope to develop for this would require stopping drinking alcohol or it creates bad side effects. Of course, stopping alcohol consumption would prevent all this liver disease in the first place. The cause is known. But medicine, as usual, doesn’t care to stop the cause, just sell a product to treat the problem.
Naturally, the researchers in this study have economic interests. From the actual study: “B.S. has consulted for Ferring Research Institute, HOST Therabiomics, Intercept Pharmaceuticals, Mabwell Therapeutics, Patara Pharmaceuticals, Surrozen and Takeda. P.H.’s institution, UC San Diego, has received research support from Nterica Bio. B.S.’s institution, UC San Diego, has received research support from Axial Biotherapeutics, BiomX, ChromoLogic, CymaBay Therapeutics, NGM Biopharmaceuticals, Prodigy Biotech and Synlogic Operating Company. B.S. is the founder of Nterica Bio. UC San Diego has filed several patents with C.L., C.L.H., Y.D. and B.S. listed as inventors related to this work. M.A.F. is the founder and shareholder of Celesta Therapeutics. M.K. received research support from Jansen Pharmaceuticals, Merck and Gossamer Bio and is a founder of Elgia Bio. The other authors declare no competing interests.”
Clearly, there is more money made by selling alcohol and the drugs developed to treat people who consume it, than in having a healthy, alcohol-free culture.
Every one with a brain knows alcohol and sugar damages the liver… The Chinese say all diseases enter through the mouth and nose….. Chinese say : the secret to life is ” discipline “…… “dicipline”…. Remember this word!
The Chinese say all diseases enter through the mouth and nose….. Chinese say : the secret to life is ” discipline “…… “dicipline”…. Remember this word!